The alkaloids obtainable from Vinca rosea represent one of the most productive research areas among those groups of drugs which adversely affect the growth of experimental malignancies in mammals. Initially, only some of the alkaloids obtainable from the leaves of the plant by extraction and chromatography were found to be active as oncolytic agents. It was determined that these active anti-neoplastic vinca alkaloids obtained directly from the plant were dimeric indole-dihydroindole alkaloids representable by the formula: ##STR1##
In the above formula where R.sup.1 is acetoxy, R.sup.2 is methyl, R.sup.3 is hydroxyl, R.sup.4 is ethyl and R.sup.5 is H, VLB (vincaleucoblastine, vinblastine) is represented; where R.sup.1 is acetoxy, R.sup.2 is formyl, R.sup.3 is hydroxyl, R.sup.4 is ethyl and R.sup.5 is H, vincristine (VCR, leurocristine) is represented; where R.sup.1 is acetoxy, R.sup.2 is methyl, R.sup.3 is ethyl, R.sup.4 is hydroxyl, and R.sup.5 is H, leurosidine (vinrosidine) is represented; where R.sup.1 is acetoxy, R.sup.2 is methyl or formyl, R.sup.3 is ethyl and R.sup.4 and R.sup.5 taken together form an .alpha.-epoxide ring, leurosine and leuroformine, respectively are represented. Literature references to the above alkaloids are as follows: leurosine (U.S. Pat. No. 3,370,057), VLB (U.S. Pat. No. 3,097,137), leuroformine (Belgian Pat. No. 811,110); leurosidine and leurocristine (both in U.S. Pat. No. 3,205,220).
Two of the above alkaloids, VLB and vincristine, are now marketed for the treatment of malignancies, particularly the leukemias and related diseases in humans. The two marketed alkaloids are customarily administered by the i.v. route. Two others, leurosidine and leuroformine, have been on clinical trial, either in the U.S. or in Europe.
VLB is the more abundant of the marketed alkaloids, being isolable in usually ten-fold greater quantity than vincristine. However, on a weight basis, the dose of vincristine employed in humans is about 1/8 to 1/3 that of VLB. Methods of converting VLB to vincristine are, therefore, highly desirable, and much research and considerable resources have been expended looking for such procedures. To date, only three methods of converting VLB to vincristine have appeared in the literature. These are; enzymatic oxidation with a peroxidase and H.sub.2 O.sub.2, (Gorman-U.S. Pat. No. 3,354,163); catalytic oxidation with molecular oxygen at ambient temperature in formic acid (Derwent Abstract 33812Y/19-based on Soviet Union Pat. No. 521,845); and oxidation with chromic oxide in glacial acetic acid and acetone at -60.degree. C. (U.S. Pat. No. 3,899,943). In the patent, vincristine yields of 50% based on recovered VLB are reported. This oxidation process is not without drawbacks, however. The maintenance of a low reaction temperature is difficult in a manufacturing plant; but higher temperatures are found to produce increasing quantities of undesirable by-products. In addition, Barnett et al., U.S. Pat. No. 4,110,330, have found that VLB reacts with acetone at C-5' under oxidizing conditions even at -60.degree. C. 5'-acetonyl VLB and a related dehydration product constitute undesirable by-products of the chromic acid oxidation procedure in acetone since the 5'-acetonyl compound must be separated from vincristine by chromatography, with consequent mechanical loss of desired products. Furthermore, substantial quantities of N-desformyl vincristine are produced by chromic oxide oxidation even at low temperatures. This desformyl material must be reformylated in order to maximize vincristing yields. Reformylation is an added, necessary procedure where oxidation with chromic acid results in deformylation of the oxidized product.
The perchloric acid-ferrous perchlorate hydrogen peroxide oxidation reagent and its use is described in a series of papers by Groves et al., J. Am. Chem. Soc., 96 5274 (1974); 97 7118 (1975); and 98 859, 5290 (1976).
It is an object of this invention to provide an oxidation procedure for converting VLB to vincristine which avoids the drawbacks of the prior art procedures.